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Antibody Tests - The story so far

Updated: Sep 13

Volume 6, Issue 4 | September 7, 2022 Mara G. Aspinall and Liz Ruark Sep 8

IN THIS ISSUE: The first test for Long COVID Lab staffing challenges If you want a valid test result, blow your nose first What antibody tests can do - and what they can’t New and Noteworthy To treat Long COVID, we need to be able to test for it. Here’s a start. Researchers are finally getting a sense of exactly what Long COVID is (see a recent review in the Journal of Clinical Investigation for a useful summary). At the same time, the world is also - finally - realizing how enormous a problem it is. Long COVID affects a large percentage of those who’ve been infected: Estimates vary from 5-40%. The WHO is going with 10-20%. That’s a tremendous number of people. Scripps Professor Eric Topol’s back-of-the-napkin estimate of the numbers in the US alone is at least 10 million. A June 2022 City University of NY phone survey of a representative sample of the US population backs him up: It estimated that 21.5% of folks who had had COVID more than four weeks ago still had symptoms. If they’re right, we’re talking 18.6 million people in the US with Long COVID. We desperately need treatments, and we need tests to find out who to treat with what. IncellDx just announced CE-IVD registration for the first of these tests - a simple blood test that was developed using AI and machine learning to find biomarkers for inflammation. It detects innate immunity (monocyte) dysfunction and claims 90% accuracy in identifying cases. Given the breadth of symptoms and systems involved in long COVID, we expect more and different tests to come as research continues.

Always blow your nose - and other Omicron testing tips A recent Wall Street Journal article caught our eyes - a first-person story illustrating how someone with both obvious COVID exposure AND symptoms can get both positive and negative results on an array of tests (including PCR) during the course of an Omicron infection. The big take-home: The sample matters. Folks, we’re gonna put it right out there: These tests don’t work on snot. The virus doesn’t live there - it’s in the cells lining your nose. So if you want a valid test result, blow your nose first. And then make sure you get a good, 15-second scrape with that swab inside your snoot. So snoot not snot. Got it? Good. Now go tell all your friends. It was the best of times. It was the worst of times. Staffing a clinical diagnostics laboratory has been challenging for many years - there are just not enough trained and qualified personnel. The average age of staff is 43, and the unemployment rate in 2019, before the pandemic, was 1.8%. This shortage of personnel was abundantly clear during the height of the pandemic, when labs could not keep up with the spikes in COVID testing demand. Today, the challenge is more nuanced. Labs are closing and / or laying off trained people, but the majority of those people are pandemic hires or work in areas related to COVID testing - molecular or microbiology. The needs in those areas have decreased, but the staff shortages in other areas persist - especially those related to cancer testing (including cytogenetics and histopathology). What happens next? #1 We expect increasing automation in labs to reduce the need for people manually running tests every day. #2 We hope that COVID will encourage more people to decide that lab technology / lab medicine is a great choice for their career. Food for Thought Antibody tests: What’s past may not be prologue Antibody tests (also called serology tests) have been one of the pandemic’s most confusing tools. What are they? Why were they so hot in early 2020, when many countries bought millions of them? What did we hope they would do, and why couldn’t they do it? Like a pop star who turned out to be a one-hit wonder, antibody tests disappeared from view after their initial popularity. Here’s their story. What are antibody tests? Let’s start with the basics. Antibody tests detect one of the immune system’s responses to viral attack (T-cell and B-cell tests are important too, but beyond this discussion). They look for the presence of Y-shaped proteins called antibodies in the blood. An antibody’s job is to lock onto a specific part of a specific virus, to make the virus less effective. Antibodies that can keep a virus from entering cells and reproducing are called neutralizing antibodies. Those are the real rock stars, because they can keep an infection from happening. Antibody tests have become commonplace over the last 50 years and are therefore relatively inexpensive. Two formats are in wide use: laboratory-based high-throughput ELISA instruments, which can measure the quantity of antibody present, and single-use yes/no lateral-flow strips that look like home rapid antigen tests. Why weren’t antibody tests useful in 2020? When are they useful? At the beginning of the pandemic, nations snapped up antibody tests in the hope that they would prove a cheap way to detect COVID-19 cases. With 20-20 hindsight (pun very much intended), we should have known better. Antibody tests don’t detect early disease, because it takes a while for your body to make enough antibodies to be measurable. By that time, you’ve been contagious for a while already (see below).

Quantitative ELISA-based antibody tests have three primary uses, none of which have to do with initial disease detection:

  1. To assess the immune status of patients, especially those with compromised immune systems and/or chronic conditions. Knowing that status helps guide preventative therapy and vaccination strategy.

  2. To monitor hospitalized patients with more severe disease. Strong early antibody response is a good sign, but late response can signal fatal decline.

  3. To monitor how much pre-existing protection from infection a population has, both overall and in particular sub-populations. (This is probably the only viable use for the single-use yes/no tests.)

In theory, antibody tests should be able to tell you whether you’ve been infected before and therefore have some immunity to reinfection. But there are two problems with that potential use case. One has to do with the SARS-CoV-2 virus’s annoying ability to mutate quickly; the other involves vaccination. Antibody tests - where are they now? There are 85 COVID antibody tests with a current FDA EUA. All detect some combination of antibodies to the S and/or N proteins. There are 7 tests that detect the receptor binding domain of the spike protein (RBD/S1), but only 2 of these claim to look for the all-important neutralizing antibodies that stop infection before it starts. SARS-CoV-2 variants change this region the most, and their receptor binding domains don’t look the same as they did when the tests were designed - a neutralizing antibody for Delta does not look the same as one for Omicron. As a result, tests for neutralizing antibodies quickly become obsolete. The remaining 78 antibody tests detect more stable regions across S and/or N proteins. That gives them maximum reliability, but it also means they can’t tell whether the antibodies they find are neutralizing or not. Plus, there’s the whole problem of vaccination vs. prior infection. All current vaccines are designed to generate antibodies to S protein. So if you test with one of the 56 tests that detect only-S antibodies, you won’t know whether the positive result you get is from prior infection, vaccine, or both. Survivors of natural infection generate antibodies to a wider range of viral proteins, so if you test with one of the 10 tests that detect only-N antibodies, you know a positive result confirms prior natural infection. It is also possible to identify uninfected vaccinees: They will be S protein positive and N protein negative (S+/N-). But there’s only 1 test that reports each antibody separately. In a pinch, you could combine an S-only and an N-only test, but really, are you going to bother? The whole endeavor is of limited use, generally only in epidemiological studies. Our simple conclusion - antibody tests still serve a clear but narrow purpose. Quick Hits Nasal vaccines are here…well, almost CanSino Biologics announced Chinese approval for Convidecia Air, an inhaled form of their injectable vaccine to be used as a COVID booster. In India, regulators approved a nasal vaccine from Bharat Biotech. They’re the first for now - but there are 100+ projects in development globally. The great promise of these vaccines is that they are delivered directly to where infection begins, and awaken mucosal tissue-resident memory B and T cells where and when it matters most. Almost no data has been published on these vaccines’ effectiveness in the real world. We await more with fingers crossed.

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